41 research outputs found

    Sensitive and Specific Fluorescent Probes for Functional Analysis of the Three Major Types of Mammalian ABC Transporters

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    An underlying mechanism for multi drug resistance (MDR) is up-regulation of the transmembrane ATP-binding cassette (ABC) transporter proteins. ABC transporters also determine the general fate and effect of pharmaceutical agents in the body. The three major types of ABC transporters are MDR1 (P-gp, P-glycoprotein, ABCB1), MRP1/2 (ABCC1/2) and BCRP/MXR (ABCG2) proteins. Flow cytometry (FCM) allows determination of the functional expression levels of ABC transporters in live cells, but most dyes used as indicators (rhodamine 123, DiOC2(3), calcein-AM) have limited applicability as they do not detect all three major types of ABC transporters. Dyes with broad coverage (such as doxorubicin, daunorubicin and mitoxantrone) lack sensitivity due to overall dimness and thus may yield a significant percentage of false negative results. We describe two novel fluorescent probes that are substrates for all three common types of ABC transporters and can serve as indicators of MDR in flow cytometry assays using live cells. The probes exhibit fast internalization, favorable uptake/efflux kinetics and high sensitivity of MDR detection, as established by multidrug resistance activity factor (MAF) values and Kolmogorov-Smirnov statistical analysis. Used in combination with general or specific inhibitors of ABC transporters, both dyes readily identify functional efflux and are capable of detecting small levels of efflux as well as defining the type of multidrug resistance. The assay can be applied to the screening of putative modulators of ABC transporters, facilitating rapid, reproducible, specific and relatively simple functional detection of ABC transporter activity, and ready implementation on widely available instruments

    Ring Expansion of Cyclobutylmethylcarbenium Ions to Cyclopentane or Cyclopentene Derivatives and Metal-Promoted Analogous Rearrangements

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    A midwife's journey with grief

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    �ber das magnetische Moment des Protons

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    Bristol's smart city agenda: vision, strategy, challenges and implementation

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    Health and neuropsychological functioning of dentists exposed to mercury

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    Objectives: A cross sectional survey of dentists in the west of Scotland and unmatched controls was conducted to find the effect of chronic exposure to mercury on health and cognitive functioning. Methods: 180 dentists were asked to complete a questionnaire that included items on handling of amalgam, symptoms experienced, possible influences on psychomotor function, and the 12 item general health questionnaire. Dentists were asked to complete a dental chart of their own mouths and to give samples of urine, hair, and nails for mercury analysis. Environmental measurements of mercury in dentists' surgeries were made and participants undertook a package of computerised psychomotor tests. 180 control subjects underwent a similar procedure, completing a questionnaire, having their amalgam surfaces counted, giving urine, hair, and nail samples and undergoing the psychomotor test package. Results: Dentists had, on average, urinary mercury concentrations over four times that of control subjects, but all but one dentist had urinary mercury below the Health and Safety Executive health guidance value. Dentists were significantly more likely than control subjects to have had disorders of the kidney and memory disturbance. These symptoms were not significantly associated with urinary mercury concentration. Differences were found between the psychomotor performance of dentists and controls after adjusting for age and sex, but there was no significant association between changes in psychomotor response and mercury concentrations in urine, hair, or nails. Conclusions: Several differences in health and cognitive functioning between dentists and controls were found. These differences could not be directly attributed to their exposure to mercury. However, as similar health effects are known to be associated with mercury exposure, it would be appropriate to consider a system of health surveillance of dental staff with particular emphasis on symptoms associated with mercury toxicity where there is evidence of high levels of exposure to environmental mercury

    Creating Guardians of Physiologic Birth:The Development of an Educational Initiative for Student Midwives in the Netherlands

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    Women want positive birth experiences with high quality maternity care that is neither too much, too soon, nor too little, too late. Research confirms the effectiveness of midwifery care, and the midwifery approach to birth as physiologic may counter the upward trend of the unnecessary medicalization of birth. The role of guardian of physiologic birth is seen as central to midwifery practice; however, medical hegemony has led to the subordination of midwives, which inhibits them in fulfilling the role as guardian of physiologic birth. Learning to become powerful advocates of physiologic birth creates midwives able to speak up for effective, evidence‐based maternity care and challenge the unnecessary use of obstetric intervention. Midwifery education has a role to fulfil in molding midwives who are able to assume this role. This brief report describes the development of an educational prototype aimed at increasing student midwife agency as an advocate of physiologic birth. This was done using rapid prototyping (RP) methodology, in which important stakeholders gave input and feedback during the educational design and development process. Input from stakeholders led to the inclusion of persuasive communication strategies and discussion and debate as teaching methodologies in order to increase student midwife agency to argue for physiologic birth. Reflective evidence‐based practice, using the Optimality Index‐Netherlands, allowed students to reflect on their practice while providing a framework for discussion. Working with the RP methodology allowed for the development of a prototype that reflected the needs of midwifery stakeholders and was mindful of material and human resources.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151843/1/jmwh12999.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151843/2/jmwh12999_am.pd
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